Improving Case Definitions for Severe Malaria

Perspectives T he lack of a " gold standard " defi nition for severe malaria has been a longstanding problem for both clinicians and researchers. The defi nitions currently used comprise a set of clinical and laboratory parameters associated with an increased risk of death [1,2], combined with the presence of Plasmodium falciparum parasitemia [2,3]. In young children, these criteria are predominantly altered consciousness, severe anemia, and respiratory distress [1,3]; a broader range of criteria is applicable to adolescents and adults [2]. While these criteria are sensitive in diagnosing severe malaria, they are also present in other serious illnesses. Since asymptomatic parasitemia is common in malaria-endemic areas, patients fulfi lling current World Health Organization (WHO) criteria for severe malaria [3] often have disease attributable to another cause, such as bacterial sepsis with incidental parasitemia [4], thereby limiting the specifi city of this defi nition. For a treating clinician, a sensitive but less specifi c defi nition of severe malaria is entirely appropriate. However, for research purposes, a sensitive clinical defi nition may not necessarily be appropriate, and the case defi nition should depend on the research question. For example, in a recent randomized controlled trial of quinine versus artesunate for severe malaria [5], the aim was to compare the effi cacy of two drugs in real-world resource-poor clinical settings. The primary endpoint, mortality, included all patients enrolled with a bedside clinical diagnosis of severe malaria, who were positive for P. falciparum by a rapid diagnostic test. This sensitive but less specifi c defi nition had clinical applicability, but necessitated a large sample size to overcome the loss of power from the inclusion of patients with less severe disease or severe illness unrelated to malaria. At the other end of the spectrum, studies of severe malaria pathophysiology require defi nitions with much higher specifi city to ensure accurate identifi cation of mechanisms of disease; sensitivity is less important in these situations. Such specifi city in severe malaria has been improved using extended laboratory criteria, lumbar puncture, indirect ophthalmoscopy [6], autopsy validation [7], and a high parasite density threshold [2,8]. What defi nition for severe malaria should be used when severe malaria is a study endpoint rather than an entry criterion? In vaccine trials or intervention studies designed to prevent severe disease, case defi nitions should refl ect a balance between sensitivity and specifi city. Neither of the defi nitions described above …